DPP-4: The Physiology of Incretin Degradation

 

By Mark Abrahams, MD
Reviewed by Clifton Jackness, MD, Attending Physician in Endocrinology, Lenox Hill Hospital and the Mount Sinai Medical Center, New York, NY

Take Note

• DPP-4 exists as both a membrane-bound and soluble form.
• DPP-4 may have a role in immune modulation.

After the ingestion of a meal, the gut secretes the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The results include¹:

• Glucose-dependent insulin secretion by the pancreas
• Decreased glucagon secretion by the liver
• Delayed gastric emptying
• Appetite suppression

As with any hormone, the amount of circulating GLP-1 is governed by its elimination as well as its secretion. The enzyme dipeptidyl peptidase-4 (DPP-4) is the primary agent that metabolizes these incretin hormones.² This article reviews its physiology.
DPP-4 was originally known as either the lymphocyte cell surface marker CD26 or the adenosine deaminase (ADA)-binding protein. It is a 766-amino acid serine protease that cleaves peptide hormones with a position 2 alanine or proline.³
DPP-4 exists in the body in 2 forms: 1 membrane-bound and another smaller, soluble form.³ So in addition to being widely expressed and enzymatically active on numerous cell types and different vascular beds, DPP-4 enzymatic activity has also been detected in serum, urine, seminal plasma, and amniotic fluid. Although it has been suggested that the soluble form is a result of cleavage of the membrane-bound form, this has not been proven.<sup>4

Establishing the importance of DPP-4 in incretin physiology and in the pathophysiology of type 2 diabetes began with the observation that DPP-4 could metabolize both GLP-1 and GIP in vitro.5 Subsequent studies in DPP-4-deficient rats demonstrated reduced ability to metabolize these incretin hormones, providing further evidence.6 Finally, humans with type 2 diabetes experienced rapid degradation of incretin hormones even when they were given intravenous or subcutaneous doses in experimental conditions. Hence, DPP-4 is viewed as the primary determinant of the half-life of the incretin hormones in the circulation.3
Interestingly, the role of DPP-4 in immune function is also being explored. Some of the most compelling findings have been conducted in DPP-4- deficient mice. These mice have significantly lower T-cell counts, as well as decreased amounts of T-cell-mediated tumor lysis activity. It also appears that the ability of these mice to mount an antibody response is impaired—with lower levels of IgG and IgE produced in response to antigen challenge compared with normal mice.3
A role for DPP-4 in the inflammatory response is also suggested by its association with inflammatory arthritis. Evidence in both animal models and humans has shown that the levels of DPP-4 are inversely correlated with the severity of rheumatoid arthritis in affected subjects. Taken together, both lines of evidence suggest that there is clearly some role for DPP-4 in immune function. However, it remains to be seen whether this is due to specific enzymatic activity or other noncatalytic actions.3
At present, DPP-4 is primarily known for its role in incretin degradation and its association with type 2 diabetes. However, as new data are generated, we may come to understand its function within a broader range of disease states. Studies are ongoing.</sup>

Published: 05/20/2013
References:

1. Freeman JS. Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus. Cleve Clin J Med. 2009;76(suppl 5):S12-S19.
2. Freeman JS. A physiologic and pharmacological basis for implementation of incretin hormones in the treatment of type 2 diabetes mellitus. Mayo Clin Proc. 2010;85(suppl 12):S5-S14.
3. Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care. 2007;30:1335-1343.
4. Hildebrandt M, Reutter W, Arck P, et al. A guardian angel: the involvement of dipeptidyl peptidase IV in psychoneuroendocrine function, nutrition and immune defence. Clin Sci (Lond). 2000;99:93-104.
5. Mitani H, Takimoto M, Kimura M. Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity. Jpn J Pharmacol. 2002;88:451-458.
6. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136:3585-3596.

Fuente: http://www.medpagetoday.com/resource-center/diabetes/incretin-degradation/a/39265?eun=g419731d0reun=g419731d0r